title: PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis.
abstract: We and others have shown that the dipeptide cotransporter PepT1 is expressed in immune cells, including macrophages that are in close contact with the lamina propria of the small and large intestines. In the present study, we used PepT1-knockout (KO) mice to explore the role played by PepT1 in immune cells during dextran sodium sulfate (DSS)-induced colitis. DSS treatment caused less severe body weight loss, diminished rectal bleeding, and less diarrhea in PepT1-KO mice than in wild-type (WT) animals. A histological examination of colonic sections revealed that the colonic architecture was less disrupted and the extent of immune cell infiltration into the mucosa and submucosa following DSS treatment was reduced in PepT1-KO mice compared with WT animals. Consistent with these results, the DSS-induced colitis increase in colonic myeloperoxidase activity was significantly less in PepT1-KO mice than in WT littermates. The colonic levels of mRNAs encoding the inflammatory cytokines CXCL1, interleukin (IL)-6, monocyte chemotactic protein-1, IL-12, and interferon-γ were significantly lower in DSS-treated PepT1-KO mice than in DSS-treated WT animals. Colonic immune cells from WT had significantly higher level of proinflammatory cytokines then PepT1 KO. In addition, we observed that knocking down the PepT1 expression decreases chemotaxis of immune cells recruited during intestinal inflammation. Antibiotic treatment before DSS-induced colitis eliminated the differential expression of inflammatory cytokines between WT and PepT1-KO mice. In conclusion, PepT1 in immune cells regulates the secretion of proinflammatory cytokines triggered by bacteria and/or bacterial products, and thus has an important role in the induction of colitis. PepT1 may transport small bacterial products, such as muramyl dipeptide and the tripeptide L-Ala-gamma-D-Glu-meso-DAP, into macrophages. These materials may be sensed by members of the nucleotide-binding site-leucine-rich repeat family of intracellular receptors, ultimately resulting in altered homeostasis of the intestinal microbiota.
authors.affiliation: Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA. sayyadurai@gsu.edu
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.forename: Moiz A
authors.initials: MA
authors.lastname: Charania
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Emilie
authors.initials: E
authors.lastname: Viennois
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; C489941:Slc15a1 protein, mouse; D027981:Symporters; D016264:Dextran Sulfate; D009195:Peroxidase